Liu Kunpeng, Yu Qingan, Li Hao, Xie Changming, Wu Yaohua, Ma Dakun, Sheng Ping, Dai Wenjie, Jiang Hongchi
Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University Harbin 150001, Heilongjiang, China.
Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University Harbin 150001, Heilongjiang, China.
Am J Cancer Res. 2020 Jan 1;10(1):78-94. eCollection 2020.
Papillary thyroid carcinoma (PTC) is the most common cancer of the endocrine system, which is usually associated with a favorable therapeutic response and prognosis. However, metastatic spreading occurs in around 5% of the PTC patients. Identification of molecular markers could early predict the metastatic potential, which is essential for reducing the patient's overtreatment. Baculoviral IAP Repeat Containing 7 (BIRC7) is an inhibitor of apoptosis protein (IAP) family gene that is known to be linked to tumor progression, but its role in the setting of PTC metastasis remains unknown. This study, therefore, aims to explore the role of BIRC7 in the metastasis and autophagy of PTC and elucidate its underlying molecular mechanisms. BIRC7 expression was assessed in fresh samples of human PTC and normal tissues via qRT-PCR and immunohistochemistry. In addition, BIRC7 was overexpressed and silenced in PTC cell lines followed by transmission electron microscopy, western blotting, immunofluorescence microscopy, wound healing and invasion assays. We further explored the relevance of BIRC7 using a tumor xenograft model. Our results demonstrated that BIRC7 plays a pro-invasive role in PTC. BIRC7 expression is significantly upregulated in PTC compared with matched thyroid normal tissues. In addition, we found that BIRC7 knockdown induced a significant reduction in PTC cell EMT and metastasis and , while overexpression of BIRC7 markedly enhanced PTC cell migration and invasion. Moreover, our data showed that BIRC7 was able to suppress autophagy through modulating the expression of ATG5 and BECN1, and that this suppression is responsible for BIRC7 silence induced suppression of EMT and metastasis of PTC cell. We further found that targeting both BIRC7 and mTOR enhances autophagy in PTC cells and to achieve synergistic antimetastatic efficacy and . These findings indicate that the suppression of autophagy by BIRC7 drives the invasion and metastasis of PTC cells, thus suggesting that the activation of autophagy may inhibit metastasis of PTC with high BIRC7 expression.
甲状腺乳头状癌（PTC）是内分泌系统最常见的癌症，通常具有良好的治疗反应和预后。然而，约5%的PTC患者会发生转移扩散。识别分子标志物可以早期预测转移潜能，这对于减少患者的过度治疗至关重要。含杆状病毒IAP重复序列7（BIRC7）是一种凋亡抑制蛋白（IAP）家族基因，已知与肿瘤进展有关，但其在PTC转移中的作用尚不清楚。因此，本研究旨在探讨BIRC7在PTC转移和自噬中的作用，并阐明其潜在的分子机制。通过qRT-PCR和免疫组织化学在人PTC新鲜样本和正常组织中评估BIRC7表达。此外，在PTC细胞系中过表达和沉默BIRC7，随后进行透射电子显微镜、蛋白质印迹、免疫荧光显微镜、伤口愈合和侵袭试验。我们还使用肿瘤异种移植模型进一步探讨了BIRC7的相关性。我们的结果表明，BIRC7在PTC中发挥促侵袭作用。与匹配的甲状腺正常组织相比，PTC中BIRC7表达显著上调。此外，我们发现敲低BIRC7可显著降低PTC细胞上皮-间质转化（EMT）和转移，而BIRC7过表达则显著增强PTC细胞迁移和侵袭。此外，我们的数据表明，BIRC7能够通过调节ATG5和BECN1的表达来抑制自噬，并且这种抑制作用是BIRC7沉默诱导的PTC细胞EMT和转移抑制的原因。我们进一步发现，同时靶向BIRC7和mTOR可增强PTC细胞中的自噬，并实现协同抗转移疗效。这些发现表明，BIRC7对自噬的抑制驱动了PTC细胞的侵袭和转移，因此表明自噬的激活可能抑制高BIRC7表达的PTC的转移。
